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THE UREA-CLEARANCE TEST
558 in the former group, the attacks are less to be arrested as the result of treatment.
suggest that,
likely
AGE-INCIDENCE
The
age-incidence of the disease has some bearing prognosis, for where epilepsy begins under the age of 10 the prognosis is usually worse than at any other age. Cases which occur at puberty are much on
than those which occur at the climacoutlook for the latter is better the teric, though than for the former group. With advancing years as is well known, the tendency to develop "idiopathic " epilepsy diminishes. In what may be called senile epilepsy, taking the age of 50 (for this purpose only) as the beginning of the senile period, the prognosis is probably better than in any other group. It is a truism that the longer the fits have lasted, the less chance there is of their arrest, and the prognosis so much the worse ; epilepsy not being a selflimiting disease, but rather the reverse. Every effort should therefore be made to control the fits from the first. more numerous
TRAUMATIC EPILEPSY
Traumatic epilepsy is a condition in which fits develop as the sequel to a brain injury. It does not seem that those cases in which fits occur at the time of the injury are more likely to develop epilepsy subsequently than when this is not the case. The
to the brain may affect any part of it. I mention this because I have met with a fairly widespread belief that unless the motor centre is injured epileptic attacks will not occur as a sequel. The attacks may be of any variety, either focal (Jack-
injury
or generalised. Grand mal, petit mal, or both may occur in this group of cases. Statistics vary as to the proportion of cases of head injury in which epilepsy follows as a sequel, but it is much smaller than one might expect. Percy Sargent found only 800 in 18,000 cases of head wounds. Bathe Rawling, in a smaller group of cases, found a much higher percentage of epileptic incidencenamely, 25 per cent. in a series of 425 cases. In any particular case of head injury the odds are against the development of epilepsy as a sequel. When it does occur, it will be found that in many cases the fits can be controlled by adequate medical treatment. In some instances, as Foerster and Penfield have shown, surgical intervention with removal of scar tissue will result in cessation of the fits. Where fits occur in association with severe injury of the brain, the probability of dementia occurring is considerable. In such cases the fits are likely to persist in spite of treatment.
sonian)
C. M. HINDS HOWELL, M.D., F.R.C.P., Physician, St. Bartholomew’s Hospital, and National Hospital, Queen-square.
SPECIAL ARTICLES
BY E.
HINDEN, M.B. Camb., M.R.C.P. Lond.
FORMERLY HOUSE PHYSICIAN AT ST. GEORGE’S HOSPITAT, LONDON
Tms paper contains a discussion on the ureaclearance test as elaborated by the work of Addis and Van Slyke. The observations recorded were made on 2 normal controls and 16 patients in St.
George’s Hospital.** It has long been known that the efficiency of the kidneys to keep the blood constituents at a constant level is seriously damaged in Bright’s disease, and a need was felt for some method of expressing in numerical terms the remaining power of the kidney. Such a method would materially assist the physician in following the course of a case of nephritis, and would be invaluable for prognosis ; and some such test, no matter how rough, is essential before many surgical procedures may be undertaken. In some cases, in which an acute illness, such as scarlet fever, is followed by an acute nephritis which clears up but for a slight persistent albuminuria, an expression for kidney function is needed before it is possible to say whether the kidney is permanently damaged. In searching for some one constituent to use as an indicator of kidney function, attention was soon directed to urea. This substance is physiological (that is, it is not foreign to the normal environment of the working kidney), it is present in blood and urine in easily measurable quantities, it is a nonthreshold body, and it is non-poisonous, so that for purposes of experiment it may be given in large quantities. At first it was proposed to use the urine urea alone ; but this is liable to so many fluctuations The 2 controls and 5 of the patients were seen by and I collected the specimens from them. The details of other 11 cases were collected from the medical register of hospital. All the biochemical analyses were performed in *
hospital biochemical laboratory.
to food, exercise, and urinary volume that the results obtained are not consistent. Modifications of this test, however, such as the urea percentage in urinary samples obtained after taking urea by mouth, are still in practice. Then it was proposed to use the blood-urea alone ; this was soon abandoned, for it was found that the blood-urea did not rise after one kidney had been removed and the functioning tissue had thus been reduced to half. This showed that the blood-urea level could not be used as a measure of kidney function. On theoretical considerations alone, it appears impossible to separate these two factors. The environment in which the kidney works is the blood stream, and it is evident that the results of its labours will depend upon the concentration of the urea in that stream. It is also clear that the concentration of the urine will not be, in general, independent of the volume of the urine. It was these considerations which led many workers to investigate the relations between all these factors. The first to publish results was Ambard.1 He published two numerical laws, expressing a relation between the blood-urea, the concentration of urea in the urine, and the amount of urea passed by the
owing
THE UREA-CLEARANCE TEST
me,
the the the
kidneys. His laws were as follows : When the concentration of in the urine was constant then the blood-urea varied as the square root of the urea passed ; and when the bloodurea was constant then the quantity of urea passed varied inversely as the square root of the concentration of the urea in the urine. Nowadays it is usual to express all the data in terms of blood-urea (=B), concentration of urea in the urine (=U), and the volume of urine passed in unit of time (=V). The usual unit of time is one minute. Expressed in these quantities Ambard’s law urea
becomes : —’individuals,
is constant. This constant
out for normal in cases of nephritis
can
be worked
and then the value obtained with it. This method was French clinicians during the first decades
much used by of this century.
compared
559 In
work.
America, Addis and Watanabe tried They discovered 2 that the law did
to verify this not hold good
in very many cases, and concluded that Ambard only obtained the agreement he did because his material was so scanty. They found that the law did not even give the trend of results-i.e., according to the law, when the blood-urea is constant, if the concentration of urea in the urine rises then the total quantity of urea passed should diminish, whereas it often increases. They performed many experiments, both on rabbits and human beings, in an attempt to formulate a law which would give better
agreement. After much testing, Addis and his co-workers to the conclusion that the ratio-urea in urine : blood-urea-was constant both for the individual and for the species, provided certain conditions were in force. The most important of these conditions was that the kidneys should be working at full load. It is known that there is a large reserve power in the kidneys, so that unless they are exercised to their full extent slight damage will not be apparent. Hence it is important to give urea and water by mouth, and so cause a forced diuresis. They found that the ratio fluctuated with the urine volume, but not regularly so, and that it was much more stable when the urinary volume was high-another reason for came
encouraging
diuresis.
As an example of the importance of giving urea, they worked out the ratio on a rabbit before and after ligating one ureter 3 and found no difference ; but on comparing the ratio before and after the operation, having given urea in each case, the ratio was depressed to half its former value. This was confirmed in a later piece of work.4 Here it was shown that when recovery after nephrectomy has taken place, the urea excretion can be as large as 98 per cent. of the normal, even though the amount of functioning kidney tissue, as measured by the weight of the remaining kidney post mortem, was only 66 per cent. of the total kidney tissue before the operation. The ratio was the only numerical evaluation of function that was depressed by the operation.t Finally, all this has since been confirmed on dogs.5
Let us consider the
meaning of this ratio with regard working kidney. The ratio is the result obtained by dividing the total quantity of urea excreted by the kidneys, in one minute, by the quantity of urea contained in 100 c.cm. of blood. It is therefore equal to the number of cubic centi. metres of blood cleared of urea, in one minute. Thus, expressing Addis’s results in words, it means that when the kidney is working at full pressure, then the quantity of blood cleared of urea in one minute is fixed, and is independent of the concentration of to the
in the urine. In a number of normal human this number came to 75-76 c.cm., and this has been taken as the normal figure for kidney efficiency. It is important to realise that this figure, and its explanation, as the amount of blood cleared of urea, is independent of any theory as to how the kidney performs its work. It must not be taken as meaning that actually 76 c.cm. of blood flow through the kidney, and that this quantity is completely
the
urea
beings
&dag er; Addis explains the fact that the remaining kidney was as much as 66 per cent. of the two together, before operation, on the grounds of compensatory hypertrophy. It is known 6 that this hypertrophy can take place under certain conditions. Even so, the value of the ratio was 78 per cent. after nephrectomy, instead of the expected 66 per cent. This was explained by Oliver in the same paper, who showed, on careful sectioning of the remaining kidney, that the hypertrophy affected chiefly the glomeruli and the first part of the convoluted tubules— i.e., just the secreting parts of the kidney. This means that the true functional hypertrophy was greater than the gross hypertrophy, as measured by the increase in weight of the kidney. There was no evidence of hypertrophy in the dog,5 and here the weight of the remaining kidney was 54 per cent. of the total renal tissue, and the ratio was 56 per cent. of its value before the operation.
cleared of urea ; there is evidence, based on urea estimations of the blood in renal artery and vein,7 that only 50 per cent. of the urea is cleared. This would mean that 152 c.cm. of blood flow through the kidney, losing half their urea while so doing. This by the figure for the renal blood flow is confirmed figures of the creatinine clearance.88 In another series of experiments, Addis measured the value of this ratio on rabbits of different sizes, on rabbits after experimental nephritis, and after nephrectomy, and showed9 that the value of the ratio was almost perfectly proportional to the weight of the kidney tissue, as measured post mortem. He found, too, that in human beings this ratio was not quite constant, but differed according to the size of the individual,1O This was confirmed by McKay,11 who showed that the ratio varied with the surface area of the body, and that the kidney weight also varied directly with this expression ; this was confirmed by Van Slyke 12 working on children. He showed that the ratio was proportional to the surface area, and that the weight of the kidneys was proportional to this and not to the
body-weight. It
appeared, then,
-
.
that in this
-.
ratio
-
.
clinicians
a numerical expression of the functioning power of the kidney. In order to make sure that it did not depend on factors outside the kidney, a further series of observations was taken on this ratio under different conditions. Thus it was found that both adrenaline 13 and pituitrin 14 affected it somewhat, while the ingestion of salt 15 and dextrose 16 had no effect. The taking of food increased the ratio, but only after the fourth hour ; this appears to be due to the protein alone,i7 for it has been shown that the purin diuretics have no effect on the ratio,18 while fasting 19 and low protein intake 15 lower it. In confirmation, high protein feeding raises the ratio.20 It was shown, too, that vigorous exercise would lower the ratio to 50 per cent. of its normal value,21 although it appears that mild exercise in normal people might raise it 22 ; but in nephritics even mild exercise depresses the ratio considerably.1I3
possessed
TECHNIQUE In order to get comparative results, Addis and his workers then formulated the following technique, which keeps all the foregoing factors constant 1. The test is done when the subject is in bed. 2. In order that the effects of food may be eliminated, the test is done first thing in the morning, and no breakfast is given. 3. Fifteen grammes of urea are given at 7 A.M. in 1000 c.cm. of water. Then, till 12 noon, the subject drinks 500 c.cm. of water hourly. This raises the bloodurea and causes copious diuresis. 4. Urine is collected for each of the hourly intervals, from 9-10, 10-11, and 11-12. Blood is collected about half-way in each hourly interval.
The chief objection to this technique is that it involves the patient being in hospital overnight, and three blood collections. This first condition makes it difficult to carry out the test in private practice. Also, in cases of nephritis, it disturbs the patients to collect the urine so frequently, and some of them, especially women, find difficulty in emptying the bladder completely while lying down. It must be emphasised that consistent results are obtained only when the physician himself collects the various specimens ; otherwise it often happens that the urines are not collected at the proper times. Often the patient cannot empty his bladder just at the right moment ; but this is immaterial if the
560 actual time is noted, as what is wanted is the minute is not possible to cause diuresis). All that is necessary is to collect two consecutive specimens of urine at volume, not the total quantity passed. It must be mentioned that some other workers hourly intervals, and to obtain one specimen of blood attempted to verify Addis’s work,24 but did not find mid-way between these two ; then, if V is greater than the augmentation limit of 2 c.cm. per minute, On close examination of their consistent results. the formula for maximum clearance is used, and the data it appears that they left the collection of the result and did not force to diuresis compared with 75 ; otherwise the standard nurses, specimens by clearance is calculated, and the results expressed as a withholding urea. These factors are quite sufficient to invalidate their results ; hence their criticism of percentage of 54. This technique was adopted in all the cases here Addis lacks weight. In order to make sure that there would collected. In order to simplify the technique Van Slyke and his co-workers 25 undertook a complete re-examination be no complications due to food the test was done in the morning before breakfast. At 9 o’clock the of the whole problem. They investigated the relations between the blood-urea (=B), urine-urea (=U), patient emptied his bladder, and that was discarded ; and urine volume (=V) when the kidney was not then the urine was collected at 10 and again at 11 o’clock. A sample of blood was taken at 10 working at full load. They also made the correction o’clock. In each case if the patient did not empty for surface area, by estimating the surface of the his bladder the precise time then a careful note subject from the height and weight, comparing this was taken ofat the hour, and so the minute volume area with the normal of 1-73 sq. metres, and dividing be In some cases 15 g. of urea was could calculated. the urine volumes by the factor so obtained. They beforehand in a quantity of water. given and considered the relation between V the ratio Comparisons have been made of this test with U : B. They gave the term " clearance " to the others. Thus the rise of plasma sulphates runs in 1 of blood cleared of urea min.UV/B. quantity with a fall in clearance,27 but the series was They found that, provided V was more than a limiting parallel too small to allow conclusions to be drawn. It is value, this clearance was constant both for the indimore delicate and accurate than the uric acid much vidual and for the species. In a later piece of work 26 runs parallel to the older tests for level. 28 Anaemia most showed that for individuals this they limiting kidney function,29 but this test is more delicate than value was 2 c.cm. Incidentally, this confirms Addis’s work, for the diuresis produced by 15 g. of urea the older ones, so that it gives evidence of kidney the blood does. Figures obtained always raises V above this figure, and Van Slyke’s impairment before the creatinine clearance correspond by considering same as Addis’s ratio, which is clearance is the closely to those given by urea clearance, but the therefore also shown to be constant. This limiting estimation is much more difficult to carry out.30 volume they name the " augmentation limit." Bruger and Mosenthal 31 and Van Slyke 3a both find But it was further discovered that even when the this test is the best and most delicate of all that urine volume fell below this limit, there was still a in common use. those relation between the clearance and the urine volume. It was found that the clearance varied as the square FINDINGS root of V. From this it follows that, in order to Before considering the results obtained in this compare different individuals, it is first necessary series a brief review of the literature may be approto find out what their clearances would be at some priate. The first to be noticed is the work of Addis, standard volume of urine per minute. The standard who followed up several cases from the onset of volume which they chose for this purpose was 1 c.cm. the disease to the termination in death or recovery.99 Van Slyke and his co-workers trace 67 cases of per minute, for this simplifies the arithmetic of the calculation, and also is the average normal urinary Bright’s disease 33 for long periods. There it is output (for 1 c.cm. per min.=1440 c.cm. daily, shown that in acute nephritis the clearance always which is approximately the normal output). The fell to 50 per cent., and may fall as low as 20 per cent., clearance calculated to this level of volume they but this fall has no prognostic importance ; they called the standard clearance, written Cs, and it is were, however, able to draw the important conclusion numerically obtained by the formula UV/B (for that if no improvement took place in four months if UV/B varies as V2, then UV2/B must be constant). the case was certain to end fatally. It was not The value of Cs for the normal individual is 54 c.cm., possible to draw inferences in the other types of although Bruger and Mosenthal 22 obtained higher Bright’s disease. Life could be maintained comfigures. The clearance obtained when the minute fortably on 15 per cent. of functioning tissue, but volume is above the augmentation limit they called uraemia is certain when it drops as low as 5 per cent. the maximum clearance, written Cm. Its value for It is also known that the blood-urea does not rise the normal individual is 75 c.cm. The close similarity till the clearance falls to 50 per cent.34 Van Slyke between this standard clearance formula of Van Slyke has since worked out a quick colorimetric method of and Ambard’s law is apparent when they are comevaluating the clearance.35 pared : the one is UV2/B, the other U V2/B ; and as Other workers have since published series of cases. U varies from 1-2 usually their value is nearly equal. In the United States Bruger and Mosenthal 36; in It can also be shown that the two values for the South America, Schultz Ortiz 37 ; in England, clearance are mutually consistent. Thus, let us Poulton and Ryffel 311 ; and in Italy, Lazzaro.39 All imagine a case where V was just about 2 c.cm. per these workers confirm Van Slyke’s conclusions. The minute. Then we could calculate the kidney efficiency value of the test in pregnancy and the puerperium from either formula, and the ratio between these two has been pointed out by several American investivalues would be UV/B : UV-L/B, 2 or V2 : 1 ; and as gators.40 n 42 43 In this last paper, however, Cantarow V=2 this would equal z4:1. But the ratio of and Ricchiuti find low values during normal preg. Cm : Cs is 75 : 54, or also 1-4 : 1. nancy, which values rise to the normal during the It is clear that now we have a much simpler method puerperium ; this was not found by any other worker of estimating kidney function. It is sufficient to in this field. In children the test is useful but difficult keep the subject quiet, and there is no need to give to interpret,a4 probably owing to the ditliculty of urea or to attempt diuresis (in many nephritics it finding the augmentation limit. 4:; Finally, tribute to
very
561 the test in urological surgery has been paid both in America U and in this country, 47 though opinion is not unanimous on its being the best. The results obtained at St. George’s Hospital are set out in Table I. I wish to thank the members of the honorary staff for permission to quote cases.
to have invalidated the
the clinical
results, for they closely follow
In the case of No. 16, a figure of 86 per cent. would 100 per cent. if this correction had
findings.
youth aged 13, have been nearer been made.
a
Nos. 1 and 2 were normal controls, and their figures, 103 and 93, are well within the limits of normal variation. TABLE I No. 16 was suspected of chronic nephritis on the grounds of an attack of scarlatinal nephritis and occasional albu. minuria. The test showed perfect function. No. 10 was suspected of nephritis because he had persistent pains in the back and was puffy under the eyes. The clearance was normal, and radioscopy showed lumbar osteo-arthritis. All these cases have normal function, and clinically also there was no nephritis. The next group show moderate impairment. No. 17, with a clearance of 60 per cent., had signs of nephritis, in that there was persistent albuminuria, but the blood pressure was low and there were no other signs of disease. No. 9 was a surgical case, who showed 66 per cent. of functioni in accordance with this, prostatectomy was perfectly successful. No. 7 had definite signs of general arterial disease in his legs and thorax, and actually died of a coronary thrombosis. He showed a trace of albumin in his urine, and his clearance was 48 per cent. of the S. = standard ; M. =magimum. normal. It is noteworthy that his blood-urea, without the ingestion of urea, was 0-044 per cent., which is only just In those cases where only one number stands in the while as shown by the outside the bounds of " percentage of normal" column, it means that both test he had only 50 pernormality, cent. of functional renal tissue. of urine were or and the standard maximum, specimens All the other cases show marked impairment of function, number given is the average of the two estimations and there was corresponding clinical evidence of advanced obtained. nephritis. No. 3 had bilateral hydronephrosis and polyThese cases fall into three groups, according to cystic disease. He had a clearance of 30 per cent., and was very ill. No. 4 had severe nephritis of the clinically the degree of impairment of the renal efficiency. " and her clearance was about 23 per nephrotic " type, (Table II.) cent. of the normal. In her history after leaving hospital TABLE II she showed a tendency to low-grade septic conditions. No. 5 was a severe nephritic, with a clearance of about 20 per cent. at first, which rose later to 40 per cent. No. 6 was in the terminal stages of acute haemorrhagic nephritis following tonsillitis. Her clearance at first was 16 per cent., falling six weeks later to 11 per cent. A few months later she died in uraemia. No. 8 was first diagnosed as nephritis during a pregnancy. It is not possible to say from the history whether she had nephritis before her pregnancy or whether it was the latter event which started the kidney trouble. When seen in hospital she had advanced nephritis clinically, and her clearance was about 18 per cent. No. 11 was in hospital over one year ago with severe nephritis. On admission this time her clearance was about 25 per cent. - Her illness started six years ago P.N. =Percentage of normal (averaged). with scarlatina. No. 12 was a very severe case, with a blood pressure of 235/155. Her clearance was 9 per In each specimens of urine were obtained, cent., and her vision was failing. Probably she was near uraemia. No. 13 was a nephritic, with a history of so that two estimations of kidney function were made for each test. In the majority of cases both these decapsulation performed 13 years ago. He showed signs nitrogen retention, and his clearance was 22 per cent. estimations were either standard or maximum, but of No. 14 is very similar. Her clearance was only 17 per in five cases one was standard and the other maximum. cent., and her blood pressure 240/140. No. 15 had Estimations have throughout been expressed in scarlatina 12 years ago. He had signs of advanced kidney percentages of the normal, so that it is possible to disease, with nitrogen retention. His clearance was 20 per cent., and five weeks later he died in ursemia. Postcompare results obtained in either of these forms. In two cases (Nos. 6 and 8) the differences are mortem findings include small atrophic kidneys and an considerable : the figures are 20 and 12, and 26 and enlarged heart. No. 18 had severe nephritis, with a 11. Both these patients are females, and the error clearance of 22 per cent. It was not certain whether his disease was due to the syphilis from which he was suffering is probably due to incomplete emptying of the bladder or whether it was caused by the arsenical treatment he on the first occasion. The test was repeated later had been having.
case two
"
No. 6, and the result obtained then agreed with that given by the second specimen of urine on the first occasion, bearing out this theory as to the error. In four cases (Nos. 4, 5, 6, and 7) the test was repeated after an interval. In Nos. 4, 6, and 7 the second result was very close to the first, but in No. 5 there was a wide divergence, from 20 at the first to 42 at the second occasion. This cannot be explained by an improvement in the clinical condition, which actually deteriorated. There was probably some error in the actual performance of the test. The correction for surface area was neglected. This does not appear
on
SUMMARY AND CONCLUSIONS
The development of laws concerning kidney excretion is described, leading up to Addis’s ratio and Van Slyke’s modification of it. This worker showed that if the urinary volume was greater than the " " augmentation limit of 2 c.cm. per minute, then the expression UV/B was constant, and, if not, then UV!/B was constant. It was further shown that the amount of functioning kidney tissue was proportional to the value of this constant, and therefore in cases of nephritis it gave a valuable measure of
562 the renal
damage. It is, however, not single estimation if it gives a low
safe to trust value. Various workers have shown that this estimate of kidney function follows the clinical condition of the patient better than any other. The value of the estimation afforded by the test is greatest in cases of moderate impairment, for most other tests show no difference at all in these circumstances. Thus it has been shown that at least half of the functioning tissue must be destroyed before the blood-urea rises. Eighteen people were subjected to the test, and in all cases the test was an accurate picture of the clinical condition. to
one
----------
REFERENCES
1. Ambard, L., and Weill, A. : Jour. de phys. et path. gén., 1912, xiv., 753. 2. Addis, T., and Watanabe, C. K. : Jour. Biol. Chem., 1916, xxiv., 203. 3. Addis and Watanabe : Ibid., 1917, xxviii., 251. 4. Addis Meyers and Oliver: Arch. Internal. Med., 1924, xxxiv., 243. 5. Hill, L. L.: Amer. Jour. Surg., 1933, xxi., 247. 6. McKay, McKay, and Addis : Jour. Nutrition, 1931, iv., 379. 7. Picard, J.: Thesis, Strasbourg, 1856 quoted by Peters and Van Slyke, Quantitative Clinical Chemistry, Vol. Interpretations," p. 345 et seq. 8. Holten, C., and Rehberg, P. B. : Acta Med. Scand., 1931, "
lxxiv., 479. 9. Addis and Oliver. The Renal Lesion in Bright’s Disease, New York, 1931. 10. Taylor, Drury, and Addis : Amer. Jr. Physiol., 1923, lxv., 55. 11. McKay : Arch. Internal. Med., 1932, l., 590. 12. Moller, McIntosh, and Van Slyke : Jour. Clin. Invest., 1928, vi., 467. 13. Addis, Barnet, and Shevsky : Amer. Jour. Physiol., 1918, xlvi., 39. 14. Addis, Barnet, and Shevsky : Ibid., p. 52. 15. Cope, C. L.: Jour. Clin. Invest., 1933, xii., 567. 16. Bruger, M., and Mosenthal, H. O. : Arch. Internal Med., 1932, l., 358. 17. Addis and Drury : Jour. Biol. Chem., 1923, lv., 629. 18. Page, I. H. : Jour. Clin. Invest., 1933, xii., 737. 19. Holman, R. M.: Amer. Jour. Physiol., 1933, civ., 615. 20. Keutmann, E. H., and McCann, W. S. : Jour. Clin. Invest., 1932, xi., 973. 21. McKay : Ibid., 1928, vi., 505. 22. Bruger and Mosenthal: Arch. Internal Med., 1932, l., 351. 23. Van Slyke, Alving, and Rose : Jour. Clin. Invest., 1932, xi., 1053. 24. Stander, Duncan, and Moses : Bull. Johns Hopkins Hosp., 1924, xxxv., 97. 25. Austin, Stillman, and Van Slyke : Jour. Biol. Chem., 1921, xlvi., 91. 26. Moller, McIntosh, and Van Slyke : Jour. Clin. Invest., 1928, vi., 427. 27. Wakefield, Power, and Keith : Jour. Amer. Med. Assoc., 1931, xcvii., 913. 28. Johnston, C. : Jour. Clin. Invest., 1931, ix., 555. 29. Ashe, B.: Arch. Internal Med., 1929, xliv., 506. 30. Hayman. Halsted, and Seyler : Jour. Clin. Invest., 1933, xii., 861. 31. Bruger and Mosenthal : Arch. Internal Med., 1932, l., 556. 32. Peters, J. P., and Van Slyke : Quantitative Clinical Chemistry, Vol. " Interpretations," p. 345 et seq. 33. Van Slyke, Stillman, Moller, Ehrich, McIntosh, Leiter, McKay, Hannon, Moore, and Johnston : Medicine, 1930, ix., 257. 34. McKay and McKay : Jour. Clin. Invest., 1927, iv., 127. 35. Van Slyke and Cope : Proc. Soc. Exp. Biol. and Med., 1932, xxix., 1169. 36. Bruger and Mosenthal : Arch. Internal Med., 1932, 1., 544. 37. Schultz Ortiz, G. : Semana Méd., 1933, cccci., 865. 38. Poulton, E. P., and Ryffel, J. H. : Guy’s Hosp. Reps., 1932, lxxxii., 303. 39. Lazzaro, G. : Policlinico (sez. prat.), 1932, xxxix., 1497. 40. Acosta-Sison, Barican, and Leiva : Jour. Philippine Islands Med. Assoc., 1933, xiv., 196. 41. Stander, Ashton, and Cadden : Amer. Jour. Obst. and Gyn., 1932, xxiii., 461. 42. Hurwitz, D., and Ohler, W. R.: Jour. Clin. Invest., 1932, xi., 1119. 43. Cantarow, A., and Ricchiuti, G.: Arch. Internal Med., 1933, lii., 637. 44. Schoenthal, Lurie, and Kelly : Amer. Jour. Dis. Child., 1933, xlv., 41. 45. Holt, L. E.: Ibid., 1932, xliv., 306. 46. Harding, V. J., and Urquhart, R. W. T.: Jour. of Urol., 1933, xxix.,
47. THE LANCET
1.
1934, i., 240.
HERTFORD BRITISH HOSPITAL, PARIS.-This hoswhich was founded and endowed by the late Sir Richard Wallace, has had an annual deficit since 1930, due to the increased cost of living and the necessity of providing additional accommodation. The fall in the exchange value of the pound has now reduced the income by about 40 per cent. and there is an annual deficiency of f2000. The hospital gives its services to all subjects of the Empire living in, or visiting, France.
pital,
BRITISH MEDICAL ASSOCIATION MEETING IN BOURNEMOUTH
SECTION OF SURGERY Prof. G. GREY TURNER, the president, took the chair at a meeting of this section when a paper on Physical Efficiency after Operations for Hernia read by Mr. MAX PAGE (London). In five years’ operations at St. Thomas’s Hospital, he said, the relative incidence had been 11 inguinal hernias, 1-4 femoral, and 1 ventral. He therefore took inguinal hernia as his text. In spite of all the consideration given to it, agreement about the best method of treatment had not been reached, largely because the information about late results was inadequate or inaccurate. A close and critical follow-up of all cases would reveal a far larger proportion of recurrences than was generally believed. His own confidence in the operation had been shaken by his experience with the Metropolitan Police ; for in the five-year period 1929-34, of 241 operations performed on police officers, 11-5 per cent. were for recurrence. Further investigation suggested that the true rate Block’s analysis of continental was even higher. figures gave a recurrence of 34-8 per cent. after two was
years, and this author declared that 40 to 45 per cent. of recurrences were avoidable. The majority seemed to be internal direct hernias, and the suture material used seemed to have little influence. After quoting the numbers in other reports, Mr. Page admitted that he really did not know quite what he wanted to The astonishing differences between the prove. statistics he had quoted could hardly be laid at the door of any special technique. His own conviction was that recurrence was commoner and more difficult to avoid than was generally thought. The factors influencing success were the technique and its failures,
post-operative pulmonary complications, operation on double hernias, and congenital feebleness of the musculature. Mr. G. L. KEYNES (London) declared that the only possible attitude was to aim at complete physical efficiency and deal with almost every hernia. No patient should be condemned to wear a truss after operation, and every patient, except possibly the old and infirm, should be able to carry on with his work. Out of 10,000 or 12,000 patients whom he had attended at the City of London Truss Society, only 500 or 600 had had recurrences. There was too much dependance on standardised operations, and the surgeon must possess a sufficiently large operative repertory for all cases. Incorrect diagnosis between direct and indirect hernias was a prolific cause of recurrence. All recurrence was due to failure in for if the tissues were not strong enough technique, a more elaborate operation was called for. The allegation of a hereditary tendency was merely an attempt to justify failure. He showed a number of slides of various conditions many of which illustrated the use of Gallie’s fascial suture. Mr. T. A. HiNDMARSH (Newcastle-on-Tyne) reviewed 154 cases operated on in hospital, nearly all labourers. Out of 102 patients with inguinal hernia 89 were perfectly satisfied, 9 had recurrences, and 4 had severe pain and tenderness in the scar. Twenty-three out of 26 femoral, 11 out of 13 umbilical, and 8 out of 13 ventral operations had been successful. It was nearly always possible to succeed in the important aim of saving the patient from wearing a truss. It was
suggest that,
likely
AGE-INCIDENCE
The
age-incidence of the disease has some bearing prognosis, for where epilepsy begins under the age of 10 the prognosis is usually worse than at any other age. Cases which occur at puberty are much on
than those which occur at the climacoutlook for the latter is better the teric, though than for the former group. With advancing years as is well known, the tendency to develop "idiopathic " epilepsy diminishes. In what may be called senile epilepsy, taking the age of 50 (for this purpose only) as the beginning of the senile period, the prognosis is probably better than in any other group. It is a truism that the longer the fits have lasted, the less chance there is of their arrest, and the prognosis so much the worse ; epilepsy not being a selflimiting disease, but rather the reverse. Every effort should therefore be made to control the fits from the first. more numerous
TRAUMATIC EPILEPSY
Traumatic epilepsy is a condition in which fits develop as the sequel to a brain injury. It does not seem that those cases in which fits occur at the time of the injury are more likely to develop epilepsy subsequently than when this is not the case. The
to the brain may affect any part of it. I mention this because I have met with a fairly widespread belief that unless the motor centre is injured epileptic attacks will not occur as a sequel. The attacks may be of any variety, either focal (Jack-
injury
or generalised. Grand mal, petit mal, or both may occur in this group of cases. Statistics vary as to the proportion of cases of head injury in which epilepsy follows as a sequel, but it is much smaller than one might expect. Percy Sargent found only 800 in 18,000 cases of head wounds. Bathe Rawling, in a smaller group of cases, found a much higher percentage of epileptic incidencenamely, 25 per cent. in a series of 425 cases. In any particular case of head injury the odds are against the development of epilepsy as a sequel. When it does occur, it will be found that in many cases the fits can be controlled by adequate medical treatment. In some instances, as Foerster and Penfield have shown, surgical intervention with removal of scar tissue will result in cessation of the fits. Where fits occur in association with severe injury of the brain, the probability of dementia occurring is considerable. In such cases the fits are likely to persist in spite of treatment.
sonian)
C. M. HINDS HOWELL, M.D., F.R.C.P., Physician, St. Bartholomew’s Hospital, and National Hospital, Queen-square.
SPECIAL ARTICLES
BY E.
HINDEN, M.B. Camb., M.R.C.P. Lond.
FORMERLY HOUSE PHYSICIAN AT ST. GEORGE’S HOSPITAT, LONDON
Tms paper contains a discussion on the ureaclearance test as elaborated by the work of Addis and Van Slyke. The observations recorded were made on 2 normal controls and 16 patients in St.
George’s Hospital.** It has long been known that the efficiency of the kidneys to keep the blood constituents at a constant level is seriously damaged in Bright’s disease, and a need was felt for some method of expressing in numerical terms the remaining power of the kidney. Such a method would materially assist the physician in following the course of a case of nephritis, and would be invaluable for prognosis ; and some such test, no matter how rough, is essential before many surgical procedures may be undertaken. In some cases, in which an acute illness, such as scarlet fever, is followed by an acute nephritis which clears up but for a slight persistent albuminuria, an expression for kidney function is needed before it is possible to say whether the kidney is permanently damaged. In searching for some one constituent to use as an indicator of kidney function, attention was soon directed to urea. This substance is physiological (that is, it is not foreign to the normal environment of the working kidney), it is present in blood and urine in easily measurable quantities, it is a nonthreshold body, and it is non-poisonous, so that for purposes of experiment it may be given in large quantities. At first it was proposed to use the urine urea alone ; but this is liable to so many fluctuations The 2 controls and 5 of the patients were seen by and I collected the specimens from them. The details of other 11 cases were collected from the medical register of hospital. All the biochemical analyses were performed in *
hospital biochemical laboratory.
to food, exercise, and urinary volume that the results obtained are not consistent. Modifications of this test, however, such as the urea percentage in urinary samples obtained after taking urea by mouth, are still in practice. Then it was proposed to use the blood-urea alone ; this was soon abandoned, for it was found that the blood-urea did not rise after one kidney had been removed and the functioning tissue had thus been reduced to half. This showed that the blood-urea level could not be used as a measure of kidney function. On theoretical considerations alone, it appears impossible to separate these two factors. The environment in which the kidney works is the blood stream, and it is evident that the results of its labours will depend upon the concentration of the urea in that stream. It is also clear that the concentration of the urine will not be, in general, independent of the volume of the urine. It was these considerations which led many workers to investigate the relations between all these factors. The first to publish results was Ambard.1 He published two numerical laws, expressing a relation between the blood-urea, the concentration of urea in the urine, and the amount of urea passed by the
owing
THE UREA-CLEARANCE TEST
me,
the the the
kidneys. His laws were as follows : When the concentration of in the urine was constant then the blood-urea varied as the square root of the urea passed ; and when the bloodurea was constant then the quantity of urea passed varied inversely as the square root of the concentration of the urea in the urine. Nowadays it is usual to express all the data in terms of blood-urea (=B), concentration of urea in the urine (=U), and the volume of urine passed in unit of time (=V). The usual unit of time is one minute. Expressed in these quantities Ambard’s law urea
becomes : —’individuals,
is constant. This constant
out for normal in cases of nephritis
can
be worked
and then the value obtained with it. This method was French clinicians during the first decades
much used by of this century.
compared
559 In
work.
America, Addis and Watanabe tried They discovered 2 that the law did
to verify this not hold good
in very many cases, and concluded that Ambard only obtained the agreement he did because his material was so scanty. They found that the law did not even give the trend of results-i.e., according to the law, when the blood-urea is constant, if the concentration of urea in the urine rises then the total quantity of urea passed should diminish, whereas it often increases. They performed many experiments, both on rabbits and human beings, in an attempt to formulate a law which would give better
agreement. After much testing, Addis and his co-workers to the conclusion that the ratio-urea in urine : blood-urea-was constant both for the individual and for the species, provided certain conditions were in force. The most important of these conditions was that the kidneys should be working at full load. It is known that there is a large reserve power in the kidneys, so that unless they are exercised to their full extent slight damage will not be apparent. Hence it is important to give urea and water by mouth, and so cause a forced diuresis. They found that the ratio fluctuated with the urine volume, but not regularly so, and that it was much more stable when the urinary volume was high-another reason for came
encouraging
diuresis.
As an example of the importance of giving urea, they worked out the ratio on a rabbit before and after ligating one ureter 3 and found no difference ; but on comparing the ratio before and after the operation, having given urea in each case, the ratio was depressed to half its former value. This was confirmed in a later piece of work.4 Here it was shown that when recovery after nephrectomy has taken place, the urea excretion can be as large as 98 per cent. of the normal, even though the amount of functioning kidney tissue, as measured by the weight of the remaining kidney post mortem, was only 66 per cent. of the total kidney tissue before the operation. The ratio was the only numerical evaluation of function that was depressed by the operation.t Finally, all this has since been confirmed on dogs.5
Let us consider the
meaning of this ratio with regard working kidney. The ratio is the result obtained by dividing the total quantity of urea excreted by the kidneys, in one minute, by the quantity of urea contained in 100 c.cm. of blood. It is therefore equal to the number of cubic centi. metres of blood cleared of urea, in one minute. Thus, expressing Addis’s results in words, it means that when the kidney is working at full pressure, then the quantity of blood cleared of urea in one minute is fixed, and is independent of the concentration of to the
in the urine. In a number of normal human this number came to 75-76 c.cm., and this has been taken as the normal figure for kidney efficiency. It is important to realise that this figure, and its explanation, as the amount of blood cleared of urea, is independent of any theory as to how the kidney performs its work. It must not be taken as meaning that actually 76 c.cm. of blood flow through the kidney, and that this quantity is completely
the
urea
beings
&dag er; Addis explains the fact that the remaining kidney was as much as 66 per cent. of the two together, before operation, on the grounds of compensatory hypertrophy. It is known 6 that this hypertrophy can take place under certain conditions. Even so, the value of the ratio was 78 per cent. after nephrectomy, instead of the expected 66 per cent. This was explained by Oliver in the same paper, who showed, on careful sectioning of the remaining kidney, that the hypertrophy affected chiefly the glomeruli and the first part of the convoluted tubules— i.e., just the secreting parts of the kidney. This means that the true functional hypertrophy was greater than the gross hypertrophy, as measured by the increase in weight of the kidney. There was no evidence of hypertrophy in the dog,5 and here the weight of the remaining kidney was 54 per cent. of the total renal tissue, and the ratio was 56 per cent. of its value before the operation.
cleared of urea ; there is evidence, based on urea estimations of the blood in renal artery and vein,7 that only 50 per cent. of the urea is cleared. This would mean that 152 c.cm. of blood flow through the kidney, losing half their urea while so doing. This by the figure for the renal blood flow is confirmed figures of the creatinine clearance.88 In another series of experiments, Addis measured the value of this ratio on rabbits of different sizes, on rabbits after experimental nephritis, and after nephrectomy, and showed9 that the value of the ratio was almost perfectly proportional to the weight of the kidney tissue, as measured post mortem. He found, too, that in human beings this ratio was not quite constant, but differed according to the size of the individual,1O This was confirmed by McKay,11 who showed that the ratio varied with the surface area of the body, and that the kidney weight also varied directly with this expression ; this was confirmed by Van Slyke 12 working on children. He showed that the ratio was proportional to the surface area, and that the weight of the kidneys was proportional to this and not to the
body-weight. It
appeared, then,
-
.
that in this
-.
ratio
-
.
clinicians
a numerical expression of the functioning power of the kidney. In order to make sure that it did not depend on factors outside the kidney, a further series of observations was taken on this ratio under different conditions. Thus it was found that both adrenaline 13 and pituitrin 14 affected it somewhat, while the ingestion of salt 15 and dextrose 16 had no effect. The taking of food increased the ratio, but only after the fourth hour ; this appears to be due to the protein alone,i7 for it has been shown that the purin diuretics have no effect on the ratio,18 while fasting 19 and low protein intake 15 lower it. In confirmation, high protein feeding raises the ratio.20 It was shown, too, that vigorous exercise would lower the ratio to 50 per cent. of its normal value,21 although it appears that mild exercise in normal people might raise it 22 ; but in nephritics even mild exercise depresses the ratio considerably.1I3
possessed
TECHNIQUE In order to get comparative results, Addis and his workers then formulated the following technique, which keeps all the foregoing factors constant 1. The test is done when the subject is in bed. 2. In order that the effects of food may be eliminated, the test is done first thing in the morning, and no breakfast is given. 3. Fifteen grammes of urea are given at 7 A.M. in 1000 c.cm. of water. Then, till 12 noon, the subject drinks 500 c.cm. of water hourly. This raises the bloodurea and causes copious diuresis. 4. Urine is collected for each of the hourly intervals, from 9-10, 10-11, and 11-12. Blood is collected about half-way in each hourly interval.
The chief objection to this technique is that it involves the patient being in hospital overnight, and three blood collections. This first condition makes it difficult to carry out the test in private practice. Also, in cases of nephritis, it disturbs the patients to collect the urine so frequently, and some of them, especially women, find difficulty in emptying the bladder completely while lying down. It must be emphasised that consistent results are obtained only when the physician himself collects the various specimens ; otherwise it often happens that the urines are not collected at the proper times. Often the patient cannot empty his bladder just at the right moment ; but this is immaterial if the
560 actual time is noted, as what is wanted is the minute is not possible to cause diuresis). All that is necessary is to collect two consecutive specimens of urine at volume, not the total quantity passed. It must be mentioned that some other workers hourly intervals, and to obtain one specimen of blood attempted to verify Addis’s work,24 but did not find mid-way between these two ; then, if V is greater than the augmentation limit of 2 c.cm. per minute, On close examination of their consistent results. the formula for maximum clearance is used, and the data it appears that they left the collection of the result and did not force to diuresis compared with 75 ; otherwise the standard nurses, specimens by clearance is calculated, and the results expressed as a withholding urea. These factors are quite sufficient to invalidate their results ; hence their criticism of percentage of 54. This technique was adopted in all the cases here Addis lacks weight. In order to make sure that there would collected. In order to simplify the technique Van Slyke and his co-workers 25 undertook a complete re-examination be no complications due to food the test was done in the morning before breakfast. At 9 o’clock the of the whole problem. They investigated the relations between the blood-urea (=B), urine-urea (=U), patient emptied his bladder, and that was discarded ; and urine volume (=V) when the kidney was not then the urine was collected at 10 and again at 11 o’clock. A sample of blood was taken at 10 working at full load. They also made the correction o’clock. In each case if the patient did not empty for surface area, by estimating the surface of the his bladder the precise time then a careful note subject from the height and weight, comparing this was taken ofat the hour, and so the minute volume area with the normal of 1-73 sq. metres, and dividing be In some cases 15 g. of urea was could calculated. the urine volumes by the factor so obtained. They beforehand in a quantity of water. given and considered the relation between V the ratio Comparisons have been made of this test with U : B. They gave the term " clearance " to the others. Thus the rise of plasma sulphates runs in 1 of blood cleared of urea min.UV/B. quantity with a fall in clearance,27 but the series was They found that, provided V was more than a limiting parallel too small to allow conclusions to be drawn. It is value, this clearance was constant both for the indimore delicate and accurate than the uric acid much vidual and for the species. In a later piece of work 26 runs parallel to the older tests for level. 28 Anaemia most showed that for individuals this they limiting kidney function,29 but this test is more delicate than value was 2 c.cm. Incidentally, this confirms Addis’s work, for the diuresis produced by 15 g. of urea the older ones, so that it gives evidence of kidney the blood does. Figures obtained always raises V above this figure, and Van Slyke’s impairment before the creatinine clearance correspond by considering same as Addis’s ratio, which is clearance is the closely to those given by urea clearance, but the therefore also shown to be constant. This limiting estimation is much more difficult to carry out.30 volume they name the " augmentation limit." Bruger and Mosenthal 31 and Van Slyke 3a both find But it was further discovered that even when the this test is the best and most delicate of all that urine volume fell below this limit, there was still a in common use. those relation between the clearance and the urine volume. It was found that the clearance varied as the square FINDINGS root of V. From this it follows that, in order to Before considering the results obtained in this compare different individuals, it is first necessary series a brief review of the literature may be approto find out what their clearances would be at some priate. The first to be noticed is the work of Addis, standard volume of urine per minute. The standard who followed up several cases from the onset of volume which they chose for this purpose was 1 c.cm. the disease to the termination in death or recovery.99 Van Slyke and his co-workers trace 67 cases of per minute, for this simplifies the arithmetic of the calculation, and also is the average normal urinary Bright’s disease 33 for long periods. There it is output (for 1 c.cm. per min.=1440 c.cm. daily, shown that in acute nephritis the clearance always which is approximately the normal output). The fell to 50 per cent., and may fall as low as 20 per cent., clearance calculated to this level of volume they but this fall has no prognostic importance ; they called the standard clearance, written Cs, and it is were, however, able to draw the important conclusion numerically obtained by the formula UV/B (for that if no improvement took place in four months if UV/B varies as V2, then UV2/B must be constant). the case was certain to end fatally. It was not The value of Cs for the normal individual is 54 c.cm., possible to draw inferences in the other types of although Bruger and Mosenthal 22 obtained higher Bright’s disease. Life could be maintained comfigures. The clearance obtained when the minute fortably on 15 per cent. of functioning tissue, but volume is above the augmentation limit they called uraemia is certain when it drops as low as 5 per cent. the maximum clearance, written Cm. Its value for It is also known that the blood-urea does not rise the normal individual is 75 c.cm. The close similarity till the clearance falls to 50 per cent.34 Van Slyke between this standard clearance formula of Van Slyke has since worked out a quick colorimetric method of and Ambard’s law is apparent when they are comevaluating the clearance.35 pared : the one is UV2/B, the other U V2/B ; and as Other workers have since published series of cases. U varies from 1-2 usually their value is nearly equal. In the United States Bruger and Mosenthal 36; in It can also be shown that the two values for the South America, Schultz Ortiz 37 ; in England, clearance are mutually consistent. Thus, let us Poulton and Ryffel 311 ; and in Italy, Lazzaro.39 All imagine a case where V was just about 2 c.cm. per these workers confirm Van Slyke’s conclusions. The minute. Then we could calculate the kidney efficiency value of the test in pregnancy and the puerperium from either formula, and the ratio between these two has been pointed out by several American investivalues would be UV/B : UV-L/B, 2 or V2 : 1 ; and as gators.40 n 42 43 In this last paper, however, Cantarow V=2 this would equal z4:1. But the ratio of and Ricchiuti find low values during normal preg. Cm : Cs is 75 : 54, or also 1-4 : 1. nancy, which values rise to the normal during the It is clear that now we have a much simpler method puerperium ; this was not found by any other worker of estimating kidney function. It is sufficient to in this field. In children the test is useful but difficult keep the subject quiet, and there is no need to give to interpret,a4 probably owing to the ditliculty of urea or to attempt diuresis (in many nephritics it finding the augmentation limit. 4:; Finally, tribute to
very
561 the test in urological surgery has been paid both in America U and in this country, 47 though opinion is not unanimous on its being the best. The results obtained at St. George’s Hospital are set out in Table I. I wish to thank the members of the honorary staff for permission to quote cases.
to have invalidated the
the clinical
results, for they closely follow
In the case of No. 16, a figure of 86 per cent. would 100 per cent. if this correction had
findings.
youth aged 13, have been nearer been made.
a
Nos. 1 and 2 were normal controls, and their figures, 103 and 93, are well within the limits of normal variation. TABLE I No. 16 was suspected of chronic nephritis on the grounds of an attack of scarlatinal nephritis and occasional albu. minuria. The test showed perfect function. No. 10 was suspected of nephritis because he had persistent pains in the back and was puffy under the eyes. The clearance was normal, and radioscopy showed lumbar osteo-arthritis. All these cases have normal function, and clinically also there was no nephritis. The next group show moderate impairment. No. 17, with a clearance of 60 per cent., had signs of nephritis, in that there was persistent albuminuria, but the blood pressure was low and there were no other signs of disease. No. 9 was a surgical case, who showed 66 per cent. of functioni in accordance with this, prostatectomy was perfectly successful. No. 7 had definite signs of general arterial disease in his legs and thorax, and actually died of a coronary thrombosis. He showed a trace of albumin in his urine, and his clearance was 48 per cent. of the S. = standard ; M. =magimum. normal. It is noteworthy that his blood-urea, without the ingestion of urea, was 0-044 per cent., which is only just In those cases where only one number stands in the while as shown by the outside the bounds of " percentage of normal" column, it means that both test he had only 50 pernormality, cent. of functional renal tissue. of urine were or and the standard maximum, specimens All the other cases show marked impairment of function, number given is the average of the two estimations and there was corresponding clinical evidence of advanced obtained. nephritis. No. 3 had bilateral hydronephrosis and polyThese cases fall into three groups, according to cystic disease. He had a clearance of 30 per cent., and was very ill. No. 4 had severe nephritis of the clinically the degree of impairment of the renal efficiency. " and her clearance was about 23 per nephrotic " type, (Table II.) cent. of the normal. In her history after leaving hospital TABLE II she showed a tendency to low-grade septic conditions. No. 5 was a severe nephritic, with a clearance of about 20 per cent. at first, which rose later to 40 per cent. No. 6 was in the terminal stages of acute haemorrhagic nephritis following tonsillitis. Her clearance at first was 16 per cent., falling six weeks later to 11 per cent. A few months later she died in uraemia. No. 8 was first diagnosed as nephritis during a pregnancy. It is not possible to say from the history whether she had nephritis before her pregnancy or whether it was the latter event which started the kidney trouble. When seen in hospital she had advanced nephritis clinically, and her clearance was about 18 per cent. No. 11 was in hospital over one year ago with severe nephritis. On admission this time her clearance was about 25 per cent. - Her illness started six years ago P.N. =Percentage of normal (averaged). with scarlatina. No. 12 was a very severe case, with a blood pressure of 235/155. Her clearance was 9 per In each specimens of urine were obtained, cent., and her vision was failing. Probably she was near uraemia. No. 13 was a nephritic, with a history of so that two estimations of kidney function were made for each test. In the majority of cases both these decapsulation performed 13 years ago. He showed signs nitrogen retention, and his clearance was 22 per cent. estimations were either standard or maximum, but of No. 14 is very similar. Her clearance was only 17 per in five cases one was standard and the other maximum. cent., and her blood pressure 240/140. No. 15 had Estimations have throughout been expressed in scarlatina 12 years ago. He had signs of advanced kidney percentages of the normal, so that it is possible to disease, with nitrogen retention. His clearance was 20 per cent., and five weeks later he died in ursemia. Postcompare results obtained in either of these forms. In two cases (Nos. 6 and 8) the differences are mortem findings include small atrophic kidneys and an considerable : the figures are 20 and 12, and 26 and enlarged heart. No. 18 had severe nephritis, with a 11. Both these patients are females, and the error clearance of 22 per cent. It was not certain whether his disease was due to the syphilis from which he was suffering is probably due to incomplete emptying of the bladder or whether it was caused by the arsenical treatment he on the first occasion. The test was repeated later had been having.
case two
"
No. 6, and the result obtained then agreed with that given by the second specimen of urine on the first occasion, bearing out this theory as to the error. In four cases (Nos. 4, 5, 6, and 7) the test was repeated after an interval. In Nos. 4, 6, and 7 the second result was very close to the first, but in No. 5 there was a wide divergence, from 20 at the first to 42 at the second occasion. This cannot be explained by an improvement in the clinical condition, which actually deteriorated. There was probably some error in the actual performance of the test. The correction for surface area was neglected. This does not appear
on
SUMMARY AND CONCLUSIONS
The development of laws concerning kidney excretion is described, leading up to Addis’s ratio and Van Slyke’s modification of it. This worker showed that if the urinary volume was greater than the " " augmentation limit of 2 c.cm. per minute, then the expression UV/B was constant, and, if not, then UV!/B was constant. It was further shown that the amount of functioning kidney tissue was proportional to the value of this constant, and therefore in cases of nephritis it gave a valuable measure of
562 the renal
damage. It is, however, not single estimation if it gives a low
safe to trust value. Various workers have shown that this estimate of kidney function follows the clinical condition of the patient better than any other. The value of the estimation afforded by the test is greatest in cases of moderate impairment, for most other tests show no difference at all in these circumstances. Thus it has been shown that at least half of the functioning tissue must be destroyed before the blood-urea rises. Eighteen people were subjected to the test, and in all cases the test was an accurate picture of the clinical condition. to
one
----------
REFERENCES
1. Ambard, L., and Weill, A. : Jour. de phys. et path. gén., 1912, xiv., 753. 2. Addis, T., and Watanabe, C. K. : Jour. Biol. Chem., 1916, xxiv., 203. 3. Addis and Watanabe : Ibid., 1917, xxviii., 251. 4. Addis Meyers and Oliver: Arch. Internal. Med., 1924, xxxiv., 243. 5. Hill, L. L.: Amer. Jour. Surg., 1933, xxi., 247. 6. McKay, McKay, and Addis : Jour. Nutrition, 1931, iv., 379. 7. Picard, J.: Thesis, Strasbourg, 1856 quoted by Peters and Van Slyke, Quantitative Clinical Chemistry, Vol. Interpretations," p. 345 et seq. 8. Holten, C., and Rehberg, P. B. : Acta Med. Scand., 1931, "
lxxiv., 479. 9. Addis and Oliver. The Renal Lesion in Bright’s Disease, New York, 1931. 10. Taylor, Drury, and Addis : Amer. Jr. Physiol., 1923, lxv., 55. 11. McKay : Arch. Internal. Med., 1932, l., 590. 12. Moller, McIntosh, and Van Slyke : Jour. Clin. Invest., 1928, vi., 467. 13. Addis, Barnet, and Shevsky : Amer. Jour. Physiol., 1918, xlvi., 39. 14. Addis, Barnet, and Shevsky : Ibid., p. 52. 15. Cope, C. L.: Jour. Clin. Invest., 1933, xii., 567. 16. Bruger, M., and Mosenthal, H. O. : Arch. Internal Med., 1932, l., 358. 17. Addis and Drury : Jour. Biol. Chem., 1923, lv., 629. 18. Page, I. H. : Jour. Clin. Invest., 1933, xii., 737. 19. Holman, R. M.: Amer. Jour. Physiol., 1933, civ., 615. 20. Keutmann, E. H., and McCann, W. S. : Jour. Clin. Invest., 1932, xi., 973. 21. McKay : Ibid., 1928, vi., 505. 22. Bruger and Mosenthal: Arch. Internal Med., 1932, l., 351. 23. Van Slyke, Alving, and Rose : Jour. Clin. Invest., 1932, xi., 1053. 24. Stander, Duncan, and Moses : Bull. Johns Hopkins Hosp., 1924, xxxv., 97. 25. Austin, Stillman, and Van Slyke : Jour. Biol. Chem., 1921, xlvi., 91. 26. Moller, McIntosh, and Van Slyke : Jour. Clin. Invest., 1928, vi., 427. 27. Wakefield, Power, and Keith : Jour. Amer. Med. Assoc., 1931, xcvii., 913. 28. Johnston, C. : Jour. Clin. Invest., 1931, ix., 555. 29. Ashe, B.: Arch. Internal Med., 1929, xliv., 506. 30. Hayman. Halsted, and Seyler : Jour. Clin. Invest., 1933, xii., 861. 31. Bruger and Mosenthal : Arch. Internal Med., 1932, l., 556. 32. Peters, J. P., and Van Slyke : Quantitative Clinical Chemistry, Vol. " Interpretations," p. 345 et seq. 33. Van Slyke, Stillman, Moller, Ehrich, McIntosh, Leiter, McKay, Hannon, Moore, and Johnston : Medicine, 1930, ix., 257. 34. McKay and McKay : Jour. Clin. Invest., 1927, iv., 127. 35. Van Slyke and Cope : Proc. Soc. Exp. Biol. and Med., 1932, xxix., 1169. 36. Bruger and Mosenthal : Arch. Internal Med., 1932, 1., 544. 37. Schultz Ortiz, G. : Semana Méd., 1933, cccci., 865. 38. Poulton, E. P., and Ryffel, J. H. : Guy’s Hosp. Reps., 1932, lxxxii., 303. 39. Lazzaro, G. : Policlinico (sez. prat.), 1932, xxxix., 1497. 40. Acosta-Sison, Barican, and Leiva : Jour. Philippine Islands Med. Assoc., 1933, xiv., 196. 41. Stander, Ashton, and Cadden : Amer. Jour. Obst. and Gyn., 1932, xxiii., 461. 42. Hurwitz, D., and Ohler, W. R.: Jour. Clin. Invest., 1932, xi., 1119. 43. Cantarow, A., and Ricchiuti, G.: Arch. Internal Med., 1933, lii., 637. 44. Schoenthal, Lurie, and Kelly : Amer. Jour. Dis. Child., 1933, xlv., 41. 45. Holt, L. E.: Ibid., 1932, xliv., 306. 46. Harding, V. J., and Urquhart, R. W. T.: Jour. of Urol., 1933, xxix.,
47. THE LANCET
1.
1934, i., 240.
HERTFORD BRITISH HOSPITAL, PARIS.-This hoswhich was founded and endowed by the late Sir Richard Wallace, has had an annual deficit since 1930, due to the increased cost of living and the necessity of providing additional accommodation. The fall in the exchange value of the pound has now reduced the income by about 40 per cent. and there is an annual deficiency of f2000. The hospital gives its services to all subjects of the Empire living in, or visiting, France.
pital,
BRITISH MEDICAL ASSOCIATION MEETING IN BOURNEMOUTH
SECTION OF SURGERY Prof. G. GREY TURNER, the president, took the chair at a meeting of this section when a paper on Physical Efficiency after Operations for Hernia read by Mr. MAX PAGE (London). In five years’ operations at St. Thomas’s Hospital, he said, the relative incidence had been 11 inguinal hernias, 1-4 femoral, and 1 ventral. He therefore took inguinal hernia as his text. In spite of all the consideration given to it, agreement about the best method of treatment had not been reached, largely because the information about late results was inadequate or inaccurate. A close and critical follow-up of all cases would reveal a far larger proportion of recurrences than was generally believed. His own confidence in the operation had been shaken by his experience with the Metropolitan Police ; for in the five-year period 1929-34, of 241 operations performed on police officers, 11-5 per cent. were for recurrence. Further investigation suggested that the true rate Block’s analysis of continental was even higher. figures gave a recurrence of 34-8 per cent. after two was
years, and this author declared that 40 to 45 per cent. of recurrences were avoidable. The majority seemed to be internal direct hernias, and the suture material used seemed to have little influence. After quoting the numbers in other reports, Mr. Page admitted that he really did not know quite what he wanted to The astonishing differences between the prove. statistics he had quoted could hardly be laid at the door of any special technique. His own conviction was that recurrence was commoner and more difficult to avoid than was generally thought. The factors influencing success were the technique and its failures,
post-operative pulmonary complications, operation on double hernias, and congenital feebleness of the musculature. Mr. G. L. KEYNES (London) declared that the only possible attitude was to aim at complete physical efficiency and deal with almost every hernia. No patient should be condemned to wear a truss after operation, and every patient, except possibly the old and infirm, should be able to carry on with his work. Out of 10,000 or 12,000 patients whom he had attended at the City of London Truss Society, only 500 or 600 had had recurrences. There was too much dependance on standardised operations, and the surgeon must possess a sufficiently large operative repertory for all cases. Incorrect diagnosis between direct and indirect hernias was a prolific cause of recurrence. All recurrence was due to failure in for if the tissues were not strong enough technique, a more elaborate operation was called for. The allegation of a hereditary tendency was merely an attempt to justify failure. He showed a number of slides of various conditions many of which illustrated the use of Gallie’s fascial suture. Mr. T. A. HiNDMARSH (Newcastle-on-Tyne) reviewed 154 cases operated on in hospital, nearly all labourers. Out of 102 patients with inguinal hernia 89 were perfectly satisfied, 9 had recurrences, and 4 had severe pain and tenderness in the scar. Twenty-three out of 26 femoral, 11 out of 13 umbilical, and 8 out of 13 ventral operations had been successful. It was nearly always possible to succeed in the important aim of saving the patient from wearing a truss. It was